Human HIV infection is a disease which evolves over a long period of time with a progressive loss of CD4+ T cells. The loss of CD4 T cell function both qualitatively and quantitatively diminishes the capacity of the host to respond to various infectious diseases. The ability to prevent the gradual loss of CD4+ T cells has been difficult to achieve to this point. However, there has been substantial interest in studying the qualitative function of CD4+ T cells as the course of disease progresses. Some studies using PBMCs have suggested that a switch in lymphokine production occurs from Th 1 to Th 2 over the course of disease and this precludes a more rapid clinical deterioration. Moreover, it has been suggested that responses to antigen can be restored in vitro by culturing cells in the presence of IL-12. The following studies will examine the regulation of lymphokine production and the ability to proliferate to defined antigens from both PBMC and purified CD4+ T cells at various stages of the disease. These studies will try to confirm earlier work provide new insights as to how the CD4+ T cell is regulated and whether its qualitative function can be altered. In a small number of experiments it appears that patients infected with HIV are unable to produce IL-4 from PBMC or CD4+ T cells in response to various mitogens or antigens. Moreover, both PBMC and CD4+ T cells were unable to respond to a panel of conserved HIV peptide antigens and this response was not altered by the addition of IL-12. Studies will be continued on a large number of patients, focusing on establishing the type of lymphokine phenotype from both PBMC's and purified CD4+ T cells. Moreover, newer cytokines will be studied to see if they affect the qualitative and quantitative function of these aforementioned cell types. Recently there has been a resurgence in the number of patients infected with Mycobacterium Tuberculosis in both HIV+ and HIV - populations. Moreover, the development of multi-drug resistant Tuberculosis has developed into a major health problem. Using the same techniques as outlined above, we will examine the functional capabilities of PBMC's and CD4+ T cells from patients infected with Tuberculosis. Understanding cytokine regulation in vitro and determining whether any functional defect exists may provide a rationale for in vivo therapy.